DESCRIPTION

THROMBATE III Antithrombin III (Human), is a sterile, non-pyrogenic concentrate of human
antithrombin (AT) in lyophilized powder form for reconstitution for intravenous injection. When
reconstituted with Sterile Water for Injection, USP, THROMBATE III has a pH of 6.0 to 7.5 and
contains 110 mEq/L to 210 mEq/L sodium, 110 mEq/L to 210 mEq/L chloride, 0.075 M to 0.125 M
alanine, and not more than 0.1 unit of heparin per 1 unit of AT. THROMBATE III contains no
preservative.

THROMBATE III is prepared from pooled units of human plasma from normal donors. The capacity of
the THROMBATE III manufacturing process to remove and/or inactivate enveloped and non-enveloped
viruses has been validated by laboratory spiking studies on a scaled down process model using a wide
range of viruses with diverse physicochemical properties. There are two dedicated virus
inactivation/removal steps included in the THROMBATE III manufacturing process: a heat treatment
step at 60°C ± 0.5°C for not less than 10 hours for virus inactivation and a nanofiltration step for
effective removal of viruses as small as 18 nm.

The THROMBATE III manufacturing process was also investigated for its capacity to decrease the
infectivity of an experimental agent of transmissible spongiformencephalopathy (TSE), considered as a
model for the variant Creutzfeldt-Jakob disease (vCJD) and Creutzfeldt-Jakob disease (CJD) agents. An
individual production step in the THROMBATE III manufacturing process has been shown to decrease
TSE infectivity of that experimental model agent. The TSE reduction step is the Effluent I to Effluent II
+ III fractionation step (6.0 log10 ). These studies provide reasonable assurance that low levels of
vCJD/CJD agent infectivity, if present in the starting material, would be removed.

DOSAGE AND ADMINISTRATION

For intravenous use after reconstitution only

Dose

Each vial of THROMBATE III has the functional activity, in International Units (units), stated on the
label of the vial. The potency assignment has been determined with a standard calibrated against a
World Health Organization antithrombin reference preparation. When prepared as directed, the
approximate final concentration is 50 units per milliliter.

A guide for dosing THROMBATE III is provided in Table 1.

Table 1: Dosing Guidelines

Regimen
(timing)

Target AT
Level

Dose (Units)

Monitor AT Level

Loading
Dose*

120% of normal†

120 % - baseline % x body
weight (kg)
1.4%

baseline

20 minutes (peak) postinjection

12 hours post-injection

pre-injection (trough)

Dose
Adjustment
(adjust as
needed)*

80% to 120% of
normal†

Target % - trough % x body
weight (kg)
1.4%

20 minutes (peak) postinjection

at least every 12 hours postinjection

pre-injection (trough)

Maintenance
Dose
(approximately
every 24
hours,
adjust as
needed)

80% to 120% of
normal†

Loading Dose x 0.6

approximately every 24
hours, as needed

*The dose calculation is based on an expected incremental in vivo recovery of 1.4 % per unit per kilogram above
baseline or trough levels.†Expressed as % normal level based on functional AT assay.

Monitor functional plasma levels of AT. [see table above and WARNINGS AND PRECAUTIONS] and
adjust subsequent dosing based on the trough level achieved with the preceding dose until
predictable peak and trough levels have been achieved, generally between 80% to 120% of
normal.(1)

Maintain plasma AT levels between 80% to 120% by administering maintenance doses of 60% of
the loading dose, administered every 24 hours. Adjust the maintenance dose and interval between
doses based on actual plasma AT levels achieved.

Individualize the exact loading and maintenance dose and/or dose intervals for each patient based on
the individual clinical conditions, response to therapy, and actual plasma AT levels achieved.
Recovery of THROMBATE III may vary by patient. For example,

The half-life of AT has been reported to be shortened following surgery,(2) hemorrhage or
acute thrombosis, and during intravenous heparin (or low molecular weight heparin)
administration.(3-6) In such conditions, monitor plasma AT levels more frequently, and
administer THROMBATE III as necessary. [see WARNINGS AND PRECAUTIONS , DRUG INTERACTIONS]

When an infusion of THROMBATE III is indicated for a patient with hereditary deficiency to
control an acute thrombotic episode or prevent thrombosis during or following surgical or
obstetrical procedures, raise the AT level to normal and maintain this level for 2 to 8 days,
depending on the indication for treatment, type and extent of surgery, patient’s medical condition,
past history and physician’s judgment. Base the concomitant administration of heparin in each of
these situations on the medical judgment of the physician. [see DRUG INTERACTIONS]

Reconstitution

Warm THROMBATE III and Sterile Water for Injection, USP (diluent) vials to room temperature
before reconstitution.

Remove shrink band from the THROMBATE III vial. If the shrink band is absent or shows signs of
tampering, do not use the product and notify Grifols Therapeutics Inc. immediately.

Remove the plastic flip top from each vial (Fig. A). Cleanse each vial stopper with an alcohol swab
and allow surface to dry.

Carefully remove the plastic sheath from the short end of the transfer needle. Insert the exposed
needle into the diluent vial to the hub (Fig. B).

Carefully grip the sheath of the other end of the transfer needle and twist to remove it.

Invert the diluent vial and insert the attached needle into the THROMBATE III vial at a 45° angle
(Fig. C). This will direct the stream of diluent against the wall of the vial and minimize foaming. The
vacuum will draw the diluent into the THROMBATE III vial.*

Immediately after adding the diluent, swirl the THROMBATE III vial continuously until the product
is completely dissolved (Fig. E). Some foaming may occur, but attempt to avoid excessive foaming.
Visually inspect the vial for particulate matter and discoloration prior to administration.

Clean the top of the vial of reconstituted THROMBATE III again with a new alcohol swab and let
surface dry.

Attach the filter needle (from the package) to the sterile syringe. Withdraw the THROMBATE III
solution into the syringe through the filter needle (Fig. F).

Remove the filter needle from the syringe and replace with an appropriate injection or butterfly
needle for administration.

If the same patient is using more than one vial of THROMBATE III, draw the contents of multiple
vials into the same syringe through the filter needles provided.

* If vacuum is lost in the THROMBATE III vial during reconstitution, use a sterile syringe to
remove the sterile water from the diluent vial and inject it into the THROMBATE III vial,
directing the stream of fluid against the wall of the vial.

Administration

Administer THROMBATE III, once reconstituted, alone without mixing with other agents
or diluents.

Administer within 3 hours following reconstitution. Do not refrigerate after reconstitution.

Adapt the rate of administration to the response of the individual patient, but administration of the
entire dose in 10 to 20 minutes is generally well tolerated.

HOW SUPPLIED

Dosage Forms And Strengths

THROMBATE III is a sterile lyophilized powder for reconstitution in single use vials. Each vial of
THROMBATE III contains the labeled amount of antithrombin in units per vial, typically 500 units.

When reconstituted with 10 mL of Sterile Water for Injection, USP, the final concentration is
approximately 50 units per mL.

The potency is determined with a standard calibrated in International Units against a World Health
Organization (WHO) antithrombin reference preparation.

Storage And Handling

THROMBATE III is supplied in a kit containing one single use vial of THROMBATE III lyophilized
powder for reconstitution, one vial of Sterile Water for Injection, USP, one sterile double-ended
transfer needle, and one sterile filter needle. The total activity of AT in International Units is stated on
the label of the THROMBATE III vial.

Components used in the packaging of THROMBATE III are made with natural rubber latex.

SIDE EFFECTS

In clinical studies, the most common adverse reactions (≥ 5% of subjects) were dizziness, chest
discomfort, nausea, dysgeusia, and pain (cramps).

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of one drug cannot be directly compared to rates in other clinical trials of
another drug and may not reflect the rates observed in clinical practice.

Two clinical trials were conducted in 33 subjects with congenital AT deficiency. The first was a
prospective, open-label, dose-escalation, dose-ranging, and pharmacokinetic study in 11 asymptomatic
subjects. Eight subjects received a single dose, escalated sequentially, followed by weekly dose
ranging from 25 to 125 unit/kg. Five subjects (including 2 from the first part of the study) received
weekly THROMBATE III for periods of up to 23 weeks in doses ranging from 125 to 225 unit/kg. The
second trial was a phase III, prospective, open-label study conducted in 24 subjects for additional
kinetics (n=3), the prevention of thrombosis (n=13) during high risk conditions (pregnancy, surgery), or
the treatment of thrombosis (n=10). Loading doses targeted an AT plasma level of 120% and ranged
from 33 to 150 unit/kg. Maintenance doses targeted a plasma AT range of 70% to 120%, which were 23
to 75 unit/kg.

Adverse reactions reported during the 2 clinical trials are listed in Table 2. Nine subjects (27%)
experienced 29 adverse reactions which occurred during 17 of 389 infusions. There were no serious
adverse reactions reported. The severity of adverse reactions was reported as mild or moderate, except
for wound secretion and hematoma, which was severe.

*MedDRA Preferred Term; an adverse reaction is defined as any
adverse event where either a) the event was related, or possibly
related to the drug, b) the occurrence was during infusion or
shortly after treatment, or c) the event recurred after withdrawal
and re-administration (challenge/dechallenge).†N = 33 subjects‡N = 389 infusions

During clinical investigation of THROMBATE III, there were no reports of virus transmission. None
of 12 subjects monitored for a median of 8 months (range 2–19 months) after receiving THROMBATE
III became antibody positive to human immunodeficiency virus (HIV-1). None of 14 subjects monitored
for ≥ 3 months demonstrated any evidence of hepatitis.

DRUG INTERACTIONS

The anticoagulant effect of heparin is enhanced by concurrent treatment with THROMBATE III in
patients with hereditary AT deficiency. Thus, in order to avoid bleeding, the dosage of heparin (or low
molecular weight heparin) may need to be reduced during treatment with THROMBATE III.

The effect of drugs that use antithrombin to exert their anticoagulation may be altered when
THROMBATE III is added or withdrawn. Regularly perform coagulation tests suitable for the
anticoagulant used (e.g., aPTT and anti-Factor Xa activity) and at close intervals to avoid excessive or
insufficient anticoagulation. Adjust dosage of anticoagulant as necessary. Additionally, monitor the
patients for the occurrence of bleeding or thrombosis.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, are possible. Early signs of hypersensitivity
reactions, which can progress to anaphylaxis, may include angioedema, chest tightness,
hypotension, rash, nausea, vomiting, paresthesia, restlessness, wheezing and dyspnea. If hypersensitivity
symptoms occur, discontinue use of the product immediately and administer appropriate emergency
treatment.

Transmission Of Infectious Agents

Because THROMBATE III is made from human blood, it may carry a risk of transmitting infectious
agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the
Creutzfeldt-Jakob disease (CJD) agent. There is also the possibility that unknown infectious agents may
be present in the product. The risk that the product will transmit viruses has been reduced by screening
plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus
infections, and by inactivating and removing certain viruses during manufacture. Despite these measures,
this product may still potentially transmit diseases.

Report all infections suspected by a physician possibly to have been transmitted by this product to
Grifols Therapeutics Inc. at 1-800-520-2807.

Monitoring

Laboratory Tests

The effect of drugs that use antithrombin to exert their anticoagulation may be altered when
THROMBATE III is added or withdrawn. Regularly perform coagulation tests suitable for the
anticoagulant used (e.g., aPTT and anti-Factor Xa activity) to avoid excessive or insufficient
anticoagulation. Additionally, monitor the patients for the occurrence of bleeding or thrombosis.
[see DRUG INTERACTIONS]

Measure functional levels of AT in plasma by amidolytic assays using chromogenic substrates or by
clotting assays. Do not use immunoassays because they do not detect all hereditary AT deficiencies.

Use In Specific populations

Pregnancy

Risk Summary

There are no data with THROMBATE III use in pregnant women to inform a drug-associated risk.
However, there are clinical considerations [see Clinical Considerations]. It is not known whether
THROMBATE III can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. THROMBATE III should be given to a pregnant woman only if clearly needed.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in
clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Reproduction studies have been performed in rats and rabbits at doses up to four times the human dose
and have revealed no evidence of impaired fertility or harm to the fetus due to THROMBATE III.

Clinical Considerations

Lactation

Risk Summary

There is no information regarding the presence of THROMBATE III in human milk, the effects on the
breastfed infant, or the effects on milk production. The developmental and health benefits of
breastfeeding should be considered along with the mother’s clinical need for THROMBATE III and
any potential adverse effects on the breastfed infant from THROMBATE III or from the underlying
maternal condition.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established.

Geriatric Use

The safety and effectiveness in the geriatric population have not been established.

OVERDOSE

CONTRAINDICATIONS

CLINICAL PHARMACOLOGY

Mechanism Of Action

Antithrombin, an alpha2 -glycoprotein of molecular weight 58,000, is normally present in human plasma
at a concentration of approximately 12.5 mg/dL and is the major plasma inhibitor of thrombin.
Inactivation of thrombin by AT occurs by formation of a covalent bond resulting in an inactive 1:1
stoichiometric complex between the two, involving an interaction of the active serine of thrombin and an
arginine reactive site on AT. AT is also capable of inactivating other components of the coagulation
cascade including factors IXa, Xa, XIa, and XIIa, as well as plasmin. The neutralization rate of serine
proteases by AT proceeds slowly in the absence of heparin, but is greatly accelerated in the presence
of heparin. As the therapeutic antithrombotic effect of heparin is mediated by AT, heparin in vivo is
ineffective in the absence or near absence of AT.

After administration, THROMBATE III temporarily replaces the missing AT in patients with hereditary
antithrombin deficiency.

Pharmacokinetics

In a clinical trial of THROMBATE III conducted in asymptomatic subjects with hereditary deficiency
of AT, 8 subjects were administered a single dose of THROMBATE III at doses ranging from 25
units/kg to 125 units/kg. Pharmacokinetic parameters were determined using immunologic and functional
AT assays (Table 3).

Clinical Studies

In a prospective, open-label clinical trial, 21 subjects were administered THROMBATE III for 16
prophylaxis events (n=13 subjects) and 10 for treatment of thrombosis (n=10 subjects) with 2 subjects
receiving THROMBATE III for both prophylaxis and treatment of thrombosis. None of the 13 subjects
with hereditary AT deficiency and histories of thromboembolism treated prophylactically on 16
separate occasions with THROMBATE III for high thrombotic risk situations (11 surgical procedures,
5 pregnancies and/or deliveries) developed a thrombotic complication. Heparin was administered in 3 of
the 11 surgical procedures. Two of the pregnant subjects received LMW heparin prophylactically
during the first trimester, but which was unable to maintain anti-coagulation with increasing dosages.
[see DRUG INTERACTIONS ] They experienced a thrombosis, which subsequently resolved with the
addition of THROMBATE III, and were therefore administered THROMBATE III and LMW heparin
prophylaxis weekly during the second and third trimesters, and during labor and delivery. These two
subjects did not experience a new thrombosis.

Ten subjects with hereditary AT deficiency were treated with THROMBATE III as well as heparin
(n=9) for major thrombotic or thromboembolic complications, including 4 subjects with thrombosis
during the first trimester of pregnancy. Nine subjects recovered with no additional thromboses or
extension of existing thrombosis. The tenth subject died due to complications from the original
pulmonary embolism with infarction which preceded treatment with THROMBATE III.

PATIENT INFORMATION

Hypersensitivity Reactions

Inform patients that allergic-type hypersensitivity reactions are possible and instruct them to inform their
physicians about any past or present known hypersensitivity to human plasma proteins prior to treatment
with THROMBATE III. Inform patients of the early signs of hypersensitivity reactions including hives,
generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis and to notify their
health care provider immediately if these events develop. [see WARNINGS AND PRECAUTIONS]

Transmission Of Infectious Disease

Inform patients that THROMBATE III is made from human plasma and may carry a risk of transmitting
infectious agents that can cause disease (e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD)
agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent). Inform patients that this risk has
been reduced by screening plasma donors for prior exposure to certain infectious agents, by testing the
donated plasma for markers of certain current infections, and by inactivating and/or removing pathogens
during manufacturing. [see WARNINGS AND PRECAUTIONS]

Report Problems to the Food and Drug Administration

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.